Feature: Targeting leukaemia

This feature appeared in the July/August 2009 issue of Australian Life Scientist. To subscribe to the magazine, go here.

There’s no question that targeted therapies represented a turning point in the treatment of cancer, with one of the poster children of the approach being treatments for chronic myelogenous leukaemia (CML). Where once CML was treated by the shotgun approach of chemotherapy or bone marrow transplants, since the late 1990s it’s been treated by the sniper precision of imatinib mesylate, otherwise known as Glivec in Australia and Gleevec in the United States, marketed by Novartis. Glivec inhibits only the specific tyrosine kinase enzymes that aid the uncontrolled replication of the cancerous cells. By inhibiting just these enzymes, Glivec brings CML to a grinding halt for the vast majority of patients.

But there was a catch: Glivec targets the peripheral cancerous cells but not the leukemic stem cells, so while it keeps the disease in check, it cannot eradicate it outright. Research has shown that around 44 percent of patients eventually develop a resistance to Glivec as new cells develop mutations that leave the drug ineffective.

There are two approved second line targeted drugs – Sprycel (dasanitib) and Tasigna (nilotinib) – that can be applied when Glivec begins to lose its mojo, and these, too, have proven highly effective. However, of the few dozen mutations identified that prevent Glivec from working, there remains one for which none of these second generation drugs can account: the T315I mutation, referred to by some as the ‘Achilles heel’ of tyrosine kinase inhibitors. T315I is the most common mutation, occurring in 15-20 percent of patients whose resistance to Glivec is caused by mutation.

This is where ChemGenex and its new drug, omacetaxine, steps in. “Omacetaxine is a first-in-class cetaxine with demonstrated clinical activity broadly in leukaemias,” says ChemGenex CEO, Greg Collier. Omacetaxine has a novel action and works by selectively targeting the short lived oncoproteins that are upregulated in leukemic cells: cyclin-D1 for proliferation; Mcl-1 for apoptosis; and c-Myc differentiation.

Significantly, omacetaxine not only targets peripheral cancerous cells but also the very leukemic stem cells. “This gives a real advantage because it starts to kill the residual disease sitting in the stem cell compartment,” says Collier. And this opens up some intriguing opportunities for the drug down the track.

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The first milestone, however, is to bring omacetaxine to market targeting the unmet need of patients with resistance to existing tyrosine kinase inhibitors due to the T315I mutation. Phase 2/3 clinical trials are already well underway and late stage results look promising.

ChemGenex recently announced these results at the American Society of Clinical Oncology and the European Hematology Association congresses. It found that the response rate for patients with the T315I mutation, particularly in the early chronic phase of the disease, was very high at 85 percent, and even those in the blast phase of the disease was 40 percent. Durability was also high, with one patient in the chronic phase maintaining the response for 30 months. Early results from the other trials show similarly positive figures.

ChemGenex is also undertaking a phase 2/3 trial on CML patients who are resistant to two or more kinase inhibitors, and is planning a further phase 2 study combining omacetaxine with Glivec.

Beyond CML, ChemGenex is also looking at capitalising on omacetaxine’s unique ability to target oncoproteins such as Mcl-1 for other cancers. “The fact that this drug affects these oncoproteins like Mcl-1 opens up the opportunity for the drug in other blood-borne cancers, initially myelodysplastic syndrome and acute myeloid leukaemia, and then potentially another cancer called multiple myeloma. Mcl-1 is an important oncoprotein in the development of those cancers,” says Collier.

Because there currently exist no third tier of drugs after Sprycel and Tasigna, omacetaxine received Fast Track Status FDA in the US in November 2006 and it has orphan drug status in the US and the EU. ChemGenex has already made its pre-clinical and CMC submissions to the FDA and is planning to submit the clinical section in the next few months with an aim to have the drug on the market in the US by the first quarter of 2010, and in Europe by the third quarter of 2010.

The drug will initially be available for those patients specifically with the T315I mutation, but as the other clinical trials progress, Collier hopes that omacetaxine will also be available for those who are resistant to kinase inhibitors, or even to be used in conjunction with Glivec. The market for omacetaxine has been estimated at US$500 million worldwide in 2020.

This feature appeared in the July/August 2009 issue of Australian Life Scientist. To subscribe to the magazine, go here.